Nu-substituted phenalkyl amines



United States Patent 3,202,711 N-SUBSTITUTED PHENALKYL AMINES Wolfgang Fruhstorfer, Georg Seitz, and Karl Schulte,

Dannstadt, and Heinrich Miiller, 'Pfungstadt, Germany,

assignors to E. Merck Aktiengesellschaft, Darmstadt,

Germany N0 Drawing. Filed June 19, 1963, Ser. No. 288,874

Claims priority, application-Germany, June 19, 1962,

M 53,252; June 26, 1962, M 53,338 14 Claims. (Cl. 260-570) This invention relates to the preparation of novel substituted amines. g V a The principal object of the" invent-ion is" to provide novel substituted amines as Well as the acid addition salts thereof.

Another object is to provide processes for the production of the novel compounds of this invention.

A further object is to provide pharmaceutical com positions based on the novel'arnines and salts thereof.

A still further object is to provide methodsofefiecting pharmacological activities in' mammals by administering the novel compounds of this invention.

Other objects and advantages of this invention will become apparent upon further studyof the specification and appended claims.

The novel compounds of this invention conform to substituted amines of theFormula I, as follows? X-(CHn)n-(|3H-I lI-(Y)mCH '7 R1 R4 I Ra' and'the aoidaddition salts thereof, wherein R is hydrogen, methyxl' or ethyl; 1 R is hydrogen, phenyl or X; R is phenoxy or R R is hydrogen, alkyl of 1-4 carbon atoms or hydroxyalkyl of 14 carbon atoms;

X is a substituted phenyl radical of the formula:

R is a tertiary alkyl group of 4-6 carbon atoms; R is hydrogen. or a tertiary alkyl group of 4'6- carbon atoms;

R and: R .are each hydrogen or a primary alkyl of I 14 carbon atoms; I 1

R is hydrogen or vhydroxy, with the provision that when R is hydroxy it is in other than the 2- or 6-position,

and at least one of R R and R is other than hydrogen;

Y is an alkylene group of 1-3 carbon atoms; in is aninteger from 0 to-l inclusive; and 1' n is an integer from 1 to 3 inclusive; vvithsthe'provh sion that the group (CH CHR contains less than 5 carbon atoms in total.

The tertiary alkyl group of the compounds of this invention is preferably ,attertiarybutyl group;

consisting of 2,6-dimethyl-3-hydroxy-4 tert.butyl-phenyl; 2,6-dimethyl 4-tert.butyl1pheny1; 3-tert.butyl-4-hyd-roxy- S-methyi-phenyi; 3,S-ditert.buty1-4-hydroxy phenyl and 2 methyl-3-hydroxy-4-tert.butyl-phenyl; at

7 The radical X is preferably a member of the group- Patented Aug. 24, 1965 Preferred sub-generic embodiments of, the compounds.

of this invention are:

(cngyn on-N-mronz-m.

N-n butyl N-[3 (3' tert.butylJV-hydroxy-SFmethyl-phen- Typical specific examples of the compounds of this invention in addition to those mentioned in the examples are: a a c v 3 tert.|butyl-4-hydroxy-N,N ,5 -trin1ethyl-phenethyl-amine N-ethyl-3-te1tbutyl-4-hydroxy N,S-dimethyl-phenethylamine N,N-diethyl-3-tertibutyl-4 hydroxy-S-methyLp henethyI- amine" 3tent.butyl-4 hydroxy-N,5 -dimethyl phenethy1amine N-ethyi-3 -ter=t.butyl-4-hydroxy-S-methyl-phenethylarnine 3-tent.bntyl 4-hydroxy-5-methyl N-isopropylphenethylamine t N- ('3 -tert.butyl-4-hydroxy-5 -methyl-phenethyl) -N- 1 methyl-3l',3'-diphenyl-propyl) -amine N methyl'-N- 3-tert. butyl-4hydroxy-5-methyl-pheneth- N-methyl-3-(3'-tert.Ibutyl-ft' hydroXy-ST-methylrphenyl)- propylamine" propylamine I N-isopropyl-3-(3'-tert.butyl-4'hydroxy-5'-methylphenyl) -propylarnine yl -propyl] -N-(3-p'henylpropyl) amine, N- [3-( 3 -tert.i)utyl 4 hydroxy-5 '-met'hyil-phenyl apropyl] -N-(3-phenylpropyl)-amine propyl] -N- 3phenylpropyl) -am-ine N,N -bis- 3- 33-5 -di-tert.butyl-4 hydroxy-phenyl -propyl] a-mine 7 N- aha- [3amartiniLayaw y,ma ma. pheny-D-propyH-amine I t phenyl) -propyl]-amine I dirhethylphenyD-propyl]-amine yl-lphenytl)-propyl] amine dimethyl-phenyl) -propyl] amine N-methyl-iN-( 3-phenylpropyl') -N 3 4'-tert.-bu tyl- 3 hydroXy-ZF6' dimethyl-iplienyl)-propyl]amine I The new compounds can be: produced .by any oneof V R1 R3 (IV) whereintR to R X, Y, vm and n have the previously indicated meanings.

(b) By treating with reducing agents a compound hav-- 7 ing the general structure of Formula I and containing hydrogenolytically removable moieties, or a C=N group,

or one or more non-aromatic C=C double bonds;

(c) From a compound having the general structureof Formula I but with a functionally altered hydroxy or amino group, by-liberating the hydroxy or amino group,

or by converting an amino group into a hydroxyl group by diazotizing and boiling;

(d) From a tertiary amine of Formula I by'treatment with an acid to convert the amine into a physiologically compatible acid addition salt, or conversely, from an acid addition salt of a base of Formula I by liberating the amine therefrom. V p 7 'These processes are set forth in more detail as follows:

(a) By' suitable substitution or additionzreactionsan V amine of Formula II can have added to it the group or an amine of Formula III can have added to it the group X-(CHzh-OH- I I'M or an amine of Formula I Vcan have added tolit the .group R where R to R X, Y, m

and 'n have the meanings above indicated.

For example, an amine of For'mulaII can be reacted. I I

.with a compound of Formula V V I I R2 Fion or an amine of Formula III pound of Formula VI pouncl 'of Formula VII V I I l r 4 can be reacted with a'c'om- 7 V r V 7 (v1) i or an amine of'Formula IV can be reacted with cb wherein Z represents a group which can be replaced by an amino group, and preferably the'acid residue of-an in l organic acid as for example HCl, I-IBr, HI, H 50 H PO or an organic sulfonic acid as for example p-toluene sulfonic acid; or a hydroxy; acyloxy; or a secondary or tertiary amino group.

If the chosen reaction component is an ester of one of the above mentioned acids, as for example, a halide, a dialkyl sulfate or a p-toluene sulfonic acid ester, the reaction can be performed either in the presence or in the absence of a solvent. As examples of solvents, the lower aliphatic alcohols, benzene, toluene and xylene are to be considered. Depending on which ester is used as the starting material, the work is done at low temperature, at room temperature, or at the boiling temperature of the solvent that is used. In certain cases it may be necessary toperform the reaction under pressure or at elevated temperatures. The amines of Formulas II, III and IV can be used in excess, but it can also be advantageous to perform the reaction in the presence of an acid-binding medium as, for example, an alkaline earth hydroxide or carbonate, or an organic amine that can be alkylated, if at all, only with difiiculty. Obviously the reaction conditions must be so chosen that there will not be a simultaneous etherization of phenolic hydroxyl groups.

If an alcohol (ZOH) is used, as the starting material, or if preferred a carboxylic acid ester residue of such an alcohol, the reaction with an amine of Formula II, III, or IV is preferably performed in the presence of a catalyst. As suitable catalysts, consideration can be given to dehydration or dehydrogenation catalysts or mixtures thereof, as for example, aluminum oxide or Raney nickel or noble metal catalysts such as palladium oxide or palladium charcoal.

As a starting material, use can also be made of a compound of Formula V, VI or VII where Z represents a secondary or tertiary amino group. Such an amino group under reaction conditions will react to bring about a reamination with an amine of Formula II, III, or IV. The reaction conditions for such a reamination are the usual ones. The amine of Formula II, III, or IV is preferably used in large excess and the work is done in the presence of catalysts such as acids, metal salts, iodine, dehydrating contact catalysts, hydrogenation-dehydrogenation catalysts, or sodium hydrogen sulfide. In certain cases such reamination will occur Without the use of catalysts. It is advantageous to perform the reactions in the presence of an inert solvent, as for example, benzene, under increased pressure and at higher temperature.

In Formulas V, VI and VII the substitution for the residue Z can undoubtedly be accomplished by any of the usual methods of substitution described in Houben Weyls Methoden der organischen Chemie, 4th Edition published by Georg Thieme, Stuttgart, 1957, vol. XI/ 1, pages 24 to 267.

Finally the above mentioned residues can also be introduced into the amines of Formulas II, III and IV by a suitable addition reaction. As a suitable material for this purpose, use can be made of an unsaturated com pound of Formula VIII Rs (VIII) where Y is a straight chain or branched chain alkene residue with l to 3 carbon atoms, or an olefin with 2 to 4 carbon atoms, which may be substituted by an OH group, or a compound of Formula IX where R is a straight chain or branched chain alkene residue with l to 4 carbon atoms. To the double bond of such an unsaturated compound an amine of Formula II, III or IV can be added. Such addition reactions are described on pages 267-270 of the Houben Weyl book cited above. The work is preferably done under increased pressure (up to about 300 atm.) and at elevated d temperature (up to about 300 C.). In this reaction it is advantageous to use a catalyst such as a cobalt or molybdenum catalyst or an alkali metal such as sodium and to use the secondary amine of Formula II, III or IVin excess.

The hydroxyalkyl groups are also best introduced by a conventional addition reaction. An amine of Formula III may be reacted with an alkylene oxide, preferably ethylene oxide, in the presence of a small amount of water. An inert solvent as for example, benzene or toluene may be added. The reaction mixture is either allowed to stand several hours at room temperature or is warmed a shorter or longer time up to 250 C. The reaction can also be performed under pressures up to 200 atm.

(b) according to this invention a substituted amine of Formula I can also be produced from a compound with the general structure of Formula I and which has one or more hydrogenolytically removable moieties. The conversion of such a substance into an amine of Formula I is effected by the usual hydrogenolysis. As hydrogenolytically removable moieties, the following are to be considered: halogen, diazonium, benzyl, substituted benzyl, oxygen attached to nitrogen, or an arylsulfonyl nitroso or .amino group attached to an amino group. Further examples of hydrogenolytically removable residues are hydroxy groups, esterified or etherized hydroxy groups, amino groups, or alkylated amino groups, provided these groups are next to a phenyl residue and/ or next to the nitrogen atom of the amine that was used as starting material for the hydrogenolysis.

The hydrogenolysis can be accomplished by treatment of the starting materials with catalytically activated hydrogen. As catalysts, the usual ones, as for example, the noble metal catalysts, but also Raney nickel and Raney cobalt can be employed. These catalysts can be used, for example, as oxide catalysts, as carrier catalysts, for example, palladium animal charcoal, or as finely divided metal catalysts, as for example, platinum black. The work is preferably done under increased pressure and elevated temperature. It is also advantageous to perform the reaction in the presence of an inert solvent, as for example, ethanol.

If an amine salt is used as the starting material, the hydrogenolysis can be effected in an aqueous medium.

A starting compound of the general structure of Formula I which contains an amino group as the hydrogenoly=tically removable group is obtained in all cases in which a nitrile is reacted with an amine. If the reaction is performed in the presence of catalytically activated hydrogen, the resulting amino group can be removed in a simple manner.

The secondary amine of Formula II, III or IV that is used as a reaction component is used in excess. During this reaction the nitrogen atom of the nitrile probably first forms an imino group, which is then converted into an amino group by the catalytically activated hydrogen, to be hydrogenolytically split off. The reaction is preferably performed under pressure and at elevated temperature. Any of the usual catalysts can be used, as for example, noble metal catalysts, Raney nickel catalysts or Raney cobalt.

If the starting material is a compound of the general structure of Formula I and containing a halogen atom, then the latter can be removed, not only by treatment with catalytically activated hydrogen, but also by the action of a complex metal hydride such as lithium aluminum tetrahydride, sodium boron tetrahyd-ride, or aluminurn boron hydride. Such a dehalogenation can also be performed by treatment with sodium in alcohol, magnesium in alcohol, or nickel aluminum alloy in aqueous alkali.

The same method is also suitable for the hydrogenolytic removal of hydroxyl groups which are in the alpha position to a phenyl nucleus.

It is also possible to use as the starting'material a substance having the general structure of Formula Land which preferably carries on the aromatic nucleus a diazonium group which .under'the usual deaminizing con-1 ditions can be substituted by a'hydroxyl group, as for example, in the presence of ethanol or acetone, or'in ..ly substituted aldehyde or ketone. The hydroxyl group which was first produced in this reaction by the separation of ammonia is then separated by the catalytically activated hydrogen in'the same reac'tion'. Such reductive alkylations are advantageously performed in the presence of a suitable catalyst, for which purpose the usual catalysts,

as for example, the noble metal catalysts, but also Raney nickel or Raney cobalt are to be considered, and may be used in the form of oxide catalysts, carrier catalysts, or 'finely divided metal catalysts.

The Work is preferably done under elevated hydrogen pressure (up to 200 atm.) and at elevated temperature (up to 250 C).

Such a'reductive alkylation can also be performed with num amalgam in ether-water solution.

.tions the work is preferably done in the presence of a solvent such as glacial acetic acid, benzene, toluene or chemical "reducing agents. Instead of the catalytically:

activated hydrogen, compounds, as for example, formic acid, formamide or ammonium formate may be .used. This known method of Leuckart-Wallach is set forth in de'tail in Houben-Weyl, Methoden der organischen Chemie, 4th edition, published by Georg Thieme, Stuttgart 1958, vol. XI/l, pages 648-664.

' If as a starting material, use is made of a compound having the general structure of Formula I whose amino f group is functionally altered by an aryl sulfonic' residue, then this residue can be split off by reducing agents as by treatment of. the starting material with an alkali metal in a lower aliphatic alcohol. A similar reductive split ting can also be effected by treatment of the acyl amine with an alkali metal in liquid ammonia or in an amine such as ethyl-, methyl-, or diethylamine. 'The reaction mixture is worked up in the usual manner, as for example, by treatment of the resulting product with ammonium chloride. After removal of the ammonia or the amine, the residue is taken up withwa ter and is extracted Witha solvent such as ether or chloroform. r

The starting material of this invention can also be a By catalytic hydrogenation of such an unsaturated compound under the usual conditions, the desired substituted amine of Formula I 'will be obtained. Suitable for use as hydrogenation catalysts are, for example, the noble metal catalystsor Raney nickel or Raney cobalt. For such hydrogenations,

. the conditions should not be too severe, or else the aromatic double bonds may be attacked. .The reaction temperatures should therefore not be too high. 'The work is preferably done at room temperature and in the presence of an inert solvent, as for example, a lower aliphatic alcohol such as methanol or ethanol. 'If an amine salt is used as the starting material,'the reaction can then be performed in an aqueous solution; 7

If the starting material is a compound with the general structure of Formula I "out with a G N-group, the

1 compound of the general structure of Formula 1,? but 7 V which contains a, G N-group or one or more nonaromatic C=C double bonds.

reductioncan be accomplished not only by catalytic hydrogen-ation but also by' treatment witha complex metal hydride, as forexample, lithium aluminum hydride, sodium borohydride or aluminum borohydride. The ork is preferably-done in the presenc-e of an inert solvent, but

can also be done in the presence of water. the reaction, the temperature is preferably raised to the boiling point of the solvent.

The reduction of a compound having the general 'structure of Formula I but containing a @N-grou-p can also be accomplished by nascent hydrogen which can be produced by treatment of metals with acids or bases, as for example, zinc with acid or alkali hydroxide, iron with hydrochloric acid,.or stannous chloride with hydrochloric acid. Sodium-or some other alkali metal in alcohol can also be used as the reducing agent. An aluminumnickel alloy in an aqueous alkali solution, with the possible additionof alcohol, can also be used, or also alumi- With these reacwater. The reaction can also be carried out in a heterogeneous phase, although increased pressure is generally not necessary. The reaction temperatures can be anywhere between room temperature and the boiling point of the solvent, the reaction being preferably completed by boiling the mixture under reflux. I

The new substituted amines of Formula I can also be produced by commencing with a compound having the general structure of Formula I but which contains one or more carbonyl groups which are then reduced to CH groups by the method of Wollf Kishner or by treatment with a complex metal hydride or with nascent or catalytically activated hydrogen.

The reduction according to Wollf Kishner is effected by treatment of'the starting compound with anhydrous hydrazine in absolute alcohol in an autoclave infwhich the reaction temperature is raised up to about 250 C. AS a catalyst for this reaction, sodium alcoholate is advantageously used. This reduction can also be modified according to the method of Huang Minion by using hy-' drazine hydrate as reducing agent, and the reaction is performed in a high boiling solvent miscible with water,

such as diethylene glycol or triethylene glycol, as well as in the presence of an alkali such as sodium hydroxide. The reaction mixture is boiled for some time, generally 3 to 4 hours, under reflux. The water is then distilled oif and the residue heated to about 2009 C for a while. This a will decompose the hydrazorie that has been formed while the carbonyl group that was originally present is converted into a CH group.

. If in the starting material the carbonyl group is next to an amino group, a complex metal hydride can be used as the reducing agent, such as lithium aluminum hydride, sodium 'borohydride or aluminum borohydride. The

work is prefer-ably done in the presence of an inert solvent,

and if necessary, also in the presence of water. The reaction is brought to completion by heating the mixture to boiling.

Reduction with nascent hydrogen can be eflected, for

example, by treating the starting materials with a mixture of zinc and hydrochloric acid, amalgamated zinc and hydrochloric acid, or tin and hydrochloric acid, The .work is done either with a Water-alcohol solution or in a hetero geneous phase with a mixture of water and benzene-or toluene. The reaction is brought to completion by'heatmg the reaction mixture to boiling.

Conversion of a carbonyl group into a CH group can also be effected bytreating the startingmaterial with catalytically activated hydrogen. For this purpose use is made of the usual catalysts such as the noble metal cata- The catalyst can lysts or Raney nickel or Raney cobalt. be used in the form of oxides or carrier catalysts or finely divided metal catalysts. V ample, under slightly elevated pressure and at room temperature or higher temperatures (up to about 200 C.).

If anacid amide is used as the starting material, theni copper chromium oxide catalysts can be used for the hydrogenation. The catalytic hydrogenation is prefer-. ably performed in the presence of a solvent such as meth- To complete The work is 'done, forex 9 anol or ethanol, and if necessary also with the addition of an acid such as HCl. I

(c) A compound having the general structure of Formula I with a functionally altered hydroxyl and/ or amino groups can according to this invention have its hydroxyl and/or amino groups set-free hydrolytically, alcoholytically or aminolytically. The functionally altered by droxyl group can, for example, be in the form of anO- acylor ether group, while the functionally altered amino group can, for example, be a N-acyl group. The starting compound can be subjected to an ordinary hydrolysis whereby hydroxy and amino groups would be set fiee. Such a hydrolysis can be performed in an acid or alkaline medium. The work is advantageously performed in an aqueous alcoholic medium and at the boiling temperature of the reaction solution. Forhydrolytic. splitting of ether groups, the conditions would have to be more drastic. In that case the work is done, for example, with a concentrat'ed aqueous hydfohalide solution and the reaction is perforrndat higher temperatures. The amino rou of the starting materials having fll'e general structure "of P01- inula I can also be substituted by a Mg-Halide group (containing either Cl, Br or I). The Mg-Halide group can be removed by the usual hydrolysis, for example, by treatment with dilute aqueous hydrochloric acid, or with an aqueous solution of ammonium chloride. Such startmaterials can be obtained, for example by reaction of a Shitfs base with a corresponding Grignard compound.

An esterified hydroxyl group or an amino group of a secondary amine of Formula I'that has been altered by an acyl group, as for example, an aryl'sulfonyl, ben'zoyl or acetyl group, canalso be set free alcoholytically by, for example, treating such a compound with a lower aliphatic alcohol in the presence of hydrogen chloride.

The acyl group of the amino group can also be removed aminolytically by treating the starting material, for example, in an autoclavewith ammonia or an amine such as inethylor 'ethylam'iiie; The amine or the ammonia then also serves as a solvent, and is, therefore, used in large excess. The reaction is preferably performed at a temperature of about 250C. The liberating of-thehydroxy1 group can be accomplished in a similarjmanner. For these reactions, it is in fact possible to use any of the reactions described in Houben-'Weyl, Methotlen der o'rganischen Chemie, 4th Edition, vol. XI/ 1, publieation of Georg Thieme, Stuttgart 1957, pag'es926 it.

The work can also be commenced with 'a compound of Formula I, but which instead of an OH 'gr oup'has a primary amino group which can then be converted into a hydroxyl group'by the usual diazoti'zation.

(d) A substituted amine of Formula I can be converted into a physiologically compatible acid addition salt by treatment wtih acids. The acids that should be considered for this purpose arefforexample, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and orthophosphoric acid, or organic acids such as acetic acid, propionic acid, pivalic acid, 'succinic acid, maleic acid, fumar'ic acid, lactic acid, 'malic acid, tartaric acid, citric acid, gluconic acid, L-a'scorbic acid, benzoic acid, salicyclic acid, methylsulfonic acid, 'ethyldisulfonic acid, p-toluene sulfonic acid; naphthalene disulfonic acid and S-hydroxy ethylsulfonic acid.

Conversely, it is obviously also possible to liberate a substituted amine of Formula I from its acid-addition salt by treatment withastrong base. v

If by the methods of this invention, racemic mixtures are produced, these can, if desired, be separated into their opticially active'antipodes by the usual procedures, as for example, by treatment wtih optically active acids. Such a separation can be accomplished by any of the methods described in Houben-Weyl, vol. 4/2,.pages 51-3- 519.

The compounds of this invention possess improved pharmacological properties, are characterized by a good therapeutic index, and exhibit only minor undesired side 10 efiects, thus being useful for administration to mammals; They can be used in admixture with the usual carrier materials that are used in human and veterinary medicine. The carrier materials may be such organic or inorganic substances as are suitable for parenteral, enteral or topical application and which do not enter into reaction with the new compounds, as forexample, water, vegetable oils, polyethylene glycols, gelatins, lactose, starch, magnesium stearate', talcum, Vaseline, cholesterol, etc. For parenteral application, solutions are especially suitable, and preferably oily or aqueous solutions, as .Well as suspensions or emulsions. lets or dragees can be used, whereas for topical'application salvesand cremes are used, and to which may be added antiseptics, preservatives, stabilizers, wetting agents, salts to influence the osmotic pressure, or buffer materials. I

The new compounds of this invention possess a central stimulating activity which varies largely with the various substituents of the phenyl nucleus.

In addition, some of the compounds of this invention are characterized by an outstanding anorectic activity, often combined with diuretic properties. These types of compounds are preferably those represented by the Formula I where R and R 'repre's'ent hydrogen, and R together with the group (Y) "CH does not contain more than 4 carbon atoms.

Particularly efficacious anorectic compounds are Amongthe'amines of Formula Iwith two or three aromatic groups, there are some that are very efiectivecirculatory remedies, especially those which lower the blood pressure, and spasmoly'tic agents which are characterized by the long durations of their effects. The amines of this group, and especially those with three aromatic residues also haveapronouncedcoronary widening efiect so that such compounds-could be used forthe treatment of blood circulation disorders-of the heart muscle. Certain of these compounds also have-an-antihistamine efiect. Par- For enteral application tab I and (CH2) won-111 (Y) .g-o

1 (5113* It has also been discovered that some of 'the compounds i of this invention possess pronounced bactericidal and bacteriostatic properties, especially in relation to the tubercle bacillus. These compounds are preferably those characterized" by the formula and CH3 H3045 When used as pharmaceuticals, the new compounds of the present invention maybe incorporated into pharmaceutical compositions which generally contain about 0.5- 100 mg. of the active material. Examples'for such preparations are the following:

are thoroughly mixed. The obtained powder is pressed into tablets each containing mg. of the active ingredient. V

' II) COATED TABLET Parts of 4-tert.butyl-3-hydroxy-N,N2,6 tetramethyl phenethylamine-hydrochloride Parts of lactose Q. 83 Parts of'talc 2 are thoroughly mixed and pressed into tablets in the usual way. Thetablets, each containing 15 mg. of the active ingredient, are c-oated with sugar syrup according to customary processes up to a total weight of 200 mg. per coated tablet.

of this invention are very useful antioxidants, partic- Onetablet contains:

12 (III) SUB-LINGUAL TABLET N-ethyl-N-[3-(4' tert.butyl 3' hydroxy 2',6' dimethylphenyl)-1 methyl propyl] amine hydrochloride 5 Lactose 60 Sorbitol 20 Magnesium stearate s 3 Corn starch 12 (IV) HARD GELATINE CAPSULES Hard gelatine capsules are filled with a fine powder consisting of e Parts 3-(4-tert.buty1-3'-hydroxy-2',6"- dimethylphenyl) 1- Inethyl-N-(1'-methyl 3',3 -diphenylpr0pyl) propylamine-hydrochloride 10 Lactose '85- Talc 3 Magnesium stearate 2 so that eachcapsule' contains 10 mg. of the active ingredient.

(V) COATED TABLET The inner tablet contains N-ethyl-3-(4'-tert.butyl-3' hydroxy 2,6' dimethylphenyl)-N-1-dimethylpropylarnine-hydrochloride) 15 Lactose Potato starch 5 "and is coated with sugar syrup up 200 mg. per coatedrtablet.

In an analogous manner, pharmaceutical preparations may be prepared fromthe other active compounds covered by Formula I.

For the use as bactericidal agents, the new compounds of the present invention may be mixed up with all customaryjcarrier or vehicularor filler substances and supplementary materials. ,Preferably,'they are used in aque-' ous or alcoholic-solutions containing from,,0.01 to 10% of the active ingredient. In most cases, it'is advisable to use the new amines in the form oftheir' inorganic acid addition. salts, such; as the hydrochlorides or the sulfates- Preferably preservatives such as cr esols orusual wetting agents are added,

Aside fromtheirpharmacological uses, the new amines ularly in the manufacture of rubber, synthetic fibres and resins, and in motor fuels. Furthermore, they have been found useful .in polymerization reactions by taking; up

the formed radicals. They may be used as Well as pre-' serving agents, disinfecting agents and solubilizers;

In addition, it is apparent from the foregoing specification that the secondary amines of this invention (compounds wherein R means H) are important intermediates in the preparation of the tertiary amines of this invention. These ones are highly useful in the preparation of the corresponding quaternary ammonium compounds which are highly effectivebactericides, especially those wherein the nitrogenis substituted by two lower alkyl groups and one alkyl group containing from 8 to 12 carbon atoms. Thesequaternary compounds are prepared fromthe compounds of this invention by the conventional methods for the preparation of quaternary compounds.

Without further elaboration it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The

following preferred specific embodiments are, therefore,- to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.

to a total Weight of 13 Example 1 11.0 g. 4-.tert.butyl-3hydroxy-2,6-dimethyl-phenethylamine (obtained by hydrogenation of 4-tert.butyl-3-hydroxy 2,6 dimethyl benzylcyanide (disclosed in DBP 1,117,588 of May 10, 1962),) and 10g. Raney nickel are boiled with 100 ml. ethanol hours under reflux. After cooling, the catalyst is filtered off with suction and the solvent is distilled oil. The residue is dissolved in 100 ml. ether and is shaken out with 100 ml. 5% hydrochloric acid. The starting material then crystallizes out as the hydrochloride. After filtering oil the crystals, the aqueous solution is made alkaline with a 32% NaOH solution and the basic materials isolated by extraction with ether. The crude base is converted into the hydrochloride and the latter recrystallized from alcohol-ether. The yield is 3 g. N-ethyl-4-tert.'outyl-3-hydroxy-2,6-dimethyl-phenethylafmine-hydrochloride which melts with decomposition at 264 C.

Example 2 18.5 g. phenethylbromide, 22.1 g. 4-tert.butyl-3-hydroxy-Z,6-dimethylphenethylamine and 100 ml. toluene are heated 3 hours on a steam bath. After being cooled, the hydrobromide of the starting material is removed with a suction filter. The filtrate is concentrated under vacuum and the residue converted into the hydrochloride by ether and hydrochloric acid, which hydrochloride was then extracted with benzene. The product of 6 g. of 4-tert.butyl-3-hydroxy-2,6-dimethyl-diphenethylaminehydrochloride after recrystallization from alcohol-ether had a M.P. of 217-218 C.

Example 3 22.1 g. 4-tert.butyl-3-hydroxy-2,6-dimethyl-phenethylamine and 20.8 g. diphenyl-acrolein are converted in toluene into the corresponding Schifi? base which is then hydrogenated in 600 ml. methanol and 600 ml. alcohol in the presence of 2 g. platinum oxide at normal pressure and temperature. The hydrogenated solution is reacted 'with alcoholic hydrochloric acid, the catalyst filtered off, and the solvent distilled off. After recrystallization from methanol, 2. yield of 30 g. 4-tert.butyl-3-hydnoxy-2,6- dimethyl-N-(3',3'-diphenyl-propyl)-phe11ethylamine with a M.P. of 252 C. is obtained.

Example 4 From 12 g. 4-tert.bu tyl-3hydroxy-2,6-dimethyl-phenethylamine and 19.2 g. 4,4-diphenyl-butane-2-one, the corresponding Schifi base is produced, which is then hydrogenated with 2 g.'platinum oxide in 200 ml. methanol under normal pressure and at room temperature. After being filtered and concentrated, the residue is dissolved in alcohol and is reacted to initial acidity with an ether solution of methylsulfonic acid. The solvent is distilled off, and the salt recrystallized from alcohol-petroleumether. The yield was 32 g. 4-tert.butyl-3-hydroxy-2,6- dimethyl N (1' methyl-3',3-diphenylpropyl)phenethylamine-methane-sulfonate with a M.P. of 180-182 C.

Example 5 A Schiff base that was produced from 22.1 g. 4- tert.butyl 3 hydroxyl-2,6-dimethyl-phenethylamine and 15.0 g. phenoxyacetone in 100 ml. toluene is hydrogenated with 1 g. platinum oxide in methanol under normal pressure and room temperature. The fraction that distilled at 190-200 C./0.1 Torr is converted into the hydrochloride in the usual manner. The yield was 6 g. 4- tertbutyl 3 hydroxy 2,6 dimethyl N (1' methyl- 2' phenoxyethyl)-phenethylamine-hydrochloride, which after recrystallization from benzene has a M.P. of 184- 185 C.

Example 6 22.1 g. 4-tert.butyl-3-hydroxy-2,G-dimethyI-phenethylamine and 10 g. phenoxyethylbromide are heated 4 hours to 150 C. The reaction product is dissolved in a small quantity of alcohol and after being reacted with dilute NaOH solution, is extracted with ether. After concentration of the ether solution, the crude product is distilled in vacuum and the fraction which passes over at 170-1.80 C./0.01 mm. Hg is then reacted with an equivalent amount of methylsulfonic acid in ether. The yield is 4-tert.buty l-3hydroxy-2,6-dimethyl N 2'-phenoxyethyl)-phenethylamine-methane-sulfonate which after recrystallization from alcohol-ether melts at 175 C.

Example 7 23.4 g. 4-tart.butyl-3-hydroxy-2,6-dimethyl-phenylacetone (produced by reacting 4-tert.butyl-3-hydroxy2,6-dirnethyl-benzyl-cyanide with methyl-magnesium iodide, M.P. 137-138 C.), 10 g. methylamine in methanol solution and about 300 ml. methanol are agitated 15 hours at 70 C. The reaction solution is then hydrogenated with 20 g. Raney nickel under about atm. at 70 C. The catalyst is filtered olf, the methanol distilled oil, and the residue converted into the hydrochloride. After recrystallization from alcohol-ether a yield of 17 g. 2-(4'- ter.t.butyl 3' hydroxy 2',6' dimethyl phenyl) N, 1-dimethyl-ethylamine-hydrochloride with a M.P. of 240- 242 C. is obtained.

In a similar manner other amines and salts thereof are produced by reaction of 4-tert.butyl-3-hydr0Xy-2,6-dimethylphenylacetone With (a) Isopropylarnine: yielding 2 (4' tert.butyl 3'- hydroxy 2', 6 dimethylphenyl)-1-methylrN-1-isopropylethylamine; the hydrochloride thereof melts at 251-253 C. after recrystallization from methanol-ether; (b) 3-phenylpropylarnine: yielding 2-(4'-tert.butyl-3'- hydroxy 2,6' dimethyl phenyl) 1 methyl N- (3-phenylpropyl)-ethylamine; the hydrochloride thereof melts at 182-184 C. after recrystallization from alcohol/ether;

(c) 3,3-diphenylpropylamine: yielding 2-(4'-tert.butyl- 3' hydroxy 2',6' dimethyl phenyl) 1 methyl- N-(3,3'-diphenylpropyl)-ethylamine; the hydrochloride thereof melts at 250-252 C. after recrystallization from alcohol;

(d) 1-methyl-3,3-diphenylpropylamine: yielding 2-(4'- tert.butyl 3' hydroxy 2',6' dimethyl phenyl) 1- methyl-N-(1'-rnethyl-3,3-diphenyl-propyl) ethylamine; racemate I: M.P. of the hydrochloride from ethyl acetate, 285-290 C.; racemate II: M.P. of the hydrochloride from CC1 petroleum ether, -145? C.;

(e) Ethylamine: yielding N-ethyl-Z-(4-tert.butyl-3- hydroxy-2,6'-dimethylphenyl) 1 methyl ethylamine; the hydrochloride thereof from alcohol melts at 263- 265 C.

In a similar manner from l-(4'tert.butyl-3'-hydroxy- 2',6-dimethylphenyl)-butane-2-one (produced from 4- tert.butyl 3 hydroxy 2,6 dimethylbenzyl cyanide with ethyl-magnesium bromide) and methylamine there is produced 1- ethyl-2-(4'-tert.butyl-3-hydroxy-2',6'dimethylphenyl)-N-methyl-ethylamine hydrochloride.

Example 8 Example 9 26.3 g. N-ethyl-a-(4tert.butyl-3-hydroxy-2,6-dimethylphenyl)-acetamide (M.P. -152 C., obtained from 4- t'ert.butyl 3 hydroxy 2,6 dimethyl-benzyl-cyanide by' been taken up (about 2 hours).

T raw base is converted into its hydrochloride;

15:7 saponification .followed by treatment withSOClg and ethylamine) are dissolved in 150 ml. absolute tetrahydrofuran and with cooling the solution is added drop by drop to a suspension of 12 g. LiAlH in 300 ml. absolute tetra hydrof uran, and the reaction mixture is then boiled 7 hours under reflux. 'After decomposition of the excess LiAlI-L; with water-containing tetrahydrofuran, the mixture ispoured into 2.5 litersice water, is acidified with an excess of 25% hydrochloric acid, and is extracted with ether whereby the starting material is again obtained. To

the acidaqueous solution are added 50 g. tartaric acidand the resultant mixture is poured into an excess of a cold concentrated NaOH solution. The alkaline solution is extracted with ether. The basic ingredients are converted into their hydrochlorides, from which N-ethyl-4-tert.butyl- 3-hydroxy-2,6-dimethyl-phenethylamine hydrochloride is obtained which melts at 261-264? C. with decomposition- Example 10. V

26.3 g. N-acetyl-4-tert.butyl3-hydroxy 2,6 -dimethyl- -phenethylamin'e (produced by acetylating 4-tert.butyl-3 7 hydroxy 2,6 dimethyl-phenethylamine, M.P. 123--125 C.) are reacted with LiAll-L; in tetrahydrofuran and prepared as in Example 9. Upon acidifying with'hydrochloric acid, the greater portion of it crystallizes out imme- '-diately as the hydrochloride. After recrystallization from methanol-ether, the yield is 16 g. of N-ethyl-4-tert.butyl- 3-hydroxy 2,6 dimethyl-phenethylamine-hydrochloride which melts at 263266 C. with decomposition.

Example 11 v hydroxyphenyl) propylamine (produced from 3,5 ditert.butyl 4 hydroxy benzaldehyde by reaction with cyanacetic acid to produce the corresponding cinnamic acid nitrile, followed by hydrogenation and acetylation) in 150 ml. dry ether is added drop by drop with stirring and cooling to 2.8 g. lithium-aluminum-hydride in 50 ml.

dry ether. After all of it is added, the mixture is heated to boiling one hour, is then cooled to +5 C., and is reacted with moist ether, ammonium chloride and aqueous ammonia. The ether layer is separated and after drying over sodium sulfatethe solvent is evaporated. The

Exumple 12 I 12 g. of the Schiif base produced from 4'-tert.butyl-3- hydroxy-2,6-dime'thylphenethylamine and acetone are dissolved in 200 mhmethanbl and hydrogenated. with 1.5 g. platinum oxide under normal pressure and at room temperature until the theoretical amount of hydrogen has removed by filtration, the solvent is distilled oil and the crystallization from alcohol/ether, the yield is g. 4- ,tert.butyl 3 hydroxy 2,6-dimethyl-N-i-propyl-phenyl- -ethylamine-hydrochloride, MP. 230 C.

In a similar manner there is produced:

(a) N benzyl 4 tertlbutyl 2,6 dimethyl phen After the catalyst is (d) 4 tertbutyl 3 hydroxy 2,6 -dimethyl N- (1' methyl 3. phenylpropyl)-phenethylarnine from 4- tert.butyl-3-hydroxy 2,6 dimethyl-phenethylamine and benzalacetone, which hydrochloride thereof after recrys-' tallization from benzene melts at 160162 C.

' Example 13 V The Schitf base which was produced from 23.5 g. 3-(3'- ethyl-5-tert.butyl 4'-hydroxyphenyl)-propylamine and 6.4

g. propionaldehydeis dissolved in 20 ml. absolute alcohol and then hydrogenated in the presence of 2.5 g. platinum oxide under 6 atm. at C. The solution is freed from the catalyst and is evaporated down; a little water is added to separate the oily base, which is then dissolved in ether.

After drying and evaporation of the solvent, the rawbase Starting material.p-Brorno-o-ethylphenol is con verted with isobutyleneinto 2-ethyl-4-bromo 6 tert.butyl-.

phenol. This is hydrogenated'to 2-ethyl-6-tert.butylphcnol and is converted by the method of Vilsmeier into 3- ethyl-5-tert.butyl-4-hyclroxylbenzaldehyde which by condensation with cyanacetic. acid and subsequent decar boxylation is converted into 3-ethyl-5-tert.butyl-4-hydroxy-cinnamic-acid-nitrile. Hydrogenation of this -nitrile yields 3-(3'-ethyl-5'-tert.butyl-4-hydroxylphenyl')- propylamine with a B.P. of 151-154" C. under 0.1 mm. Hg.

' Example 14 14.2 g. N-benzyl-4-tert.butyl-N-2,6-trimethyl-phenethylamine-hydrochloride (produced by benzylation and'subsequent methylation of 4-terttbutyl-2,6-dimethyl-pl1enethylamine) are hydrogenated with 4 g. 5% palladium charcoal in a methanol solution under normal pressure and at room temperature until the calculated amount of hydrogen is taken up. After filtration and concentration, the yield is 8.5 g. of 4-tert.butyl-N,2,6-trimethyl-' phenethylarnine-hydrochloride which after recrystalliza'- 21.8 g. 4-tert.butyl-2,6-dimethyl-phenylacetone (produced from 4-te'rt.butyl-2,6-dimethyl-benzyl-cyanide by reaction with'rnethyl-magnesiurn iodide as an oil with a Bl. at 0.1 mm. Hg of 9l94 C), 21.1 g. l-methyl- After re- 7 ethylamine from 4-tert.butyl 2,6 dimethyl-phenethylamine and benzaldehyde, Which'hydrochloride thereof after reerystallizationfrorn alcohol/ether melts at 249- 252 C.; V (b) N-benzyl 4 tert.butyl 3 hydroxy 2,6 dimethyl-phenethylamine from 4-tert.butyl-3 hydroxy-2,6-

chloride thereof melts at 218-220 C.

(c) 4 tert.butyl. 3 7 hydroxy 2,6 dimethyl N- '(3-phenylpropyl)-phenylethylamine from 4-tertibutyl-3- 3,3-diphenylp'ropylamine and 150 ml. toluene are boiled 2 hours under reflux; After concentration in a vacuum,

' the residue is hydrogenated with 5 g. platinum oxide in I 400 ml. methanol under normal pressure and at room 7 temperature.

24.8 g. 4-(4'-tert.butyl 3 hydroxy -'2,6' dimethyl- I phenyl)-butane-2-one (MP. 102-l03 C.," produced by dimethyl-phenethylamine and benzaldehyde, which hydroreaction of acetoacetic ester with 4-tert.butyl-3-iydroxy'- 2,6-dimethylbenzylchloride) are reacted with methylamine as inExample 15. v The yield is 225g. of 3-(4- tertbutyl 3 hydroxy. 2,6 dirnethylphenyl) N,1- dimethyl-propylamine which after recrystallization from benzene melts at C. The hydrochloride after recrystallization from alcohol/ether melts at 184-186 C. In an analogousrnanner there was produced by re- 7 After recrystallization from alco 17 action of 4-(4'-tert.butyl 3 hydroxy 2',6' dimethylphenyl) )-butane-2-one with:

(a) n-Propylamine: 3-(4'-tert.butyl-3'-hydroXy-2',6'- dimethylphenyl)-1-methyl-dipropylarnine which hydrochloride thereof melts at 125-126 C. with decomposition;

(b) n-Butylamine: N-n-butyl-3-(4'-tert.butyl- 3'-hydroxy 2,6 dimethylphenyl) 1 methyl propylamine, which crystallized from alcohol melts at 105- 106 C., while its hydrochloride from alcohol/ether melts at 175l77 C.;

(c) 1-methyl-2-phenylethylamine: 3-(4'-tert.butyl-3'- hydroxy 2',2' dimethylphenyl) 1 methyl N (1- methyl-2-phenylethyl)-propylamine which hydrochloride thereof from alcohol/ether melts at 234-236 C.;

(d) 3,3-diphenylpropylamine: 3-(4-tert.butyl-3-hydroxy 2,6' dirnethylphenyl) 1 methyl N (3,3'-

diphenylpropyl)-propylamine Which hydrochloride thereof from ethyl acetate melts at 178-179 C.;

(e) 1-methyl-3,S-diphenyl-propylamine: 3-(4'-tert. butyl 3' hydroxy 2,6' dimethylphenyl) l methyl- N (1' methyl 3,3' diphenylpropyl) propylamine, the hydrochloride of racemate I thereof crystallized from alcohol melts at 230232 C., and the hydrochloride of racemate II thereof from alcohol melts at 246248 C.;

(f) 4-tert.butyl-3-hydroxy- 2,6 dimethyl phenethylamine: N (4 tert.butyl 3 hydroxy 2,6 dimethylphenethyl) N [3 (4' tert.butyl 3' hydroxy 2',6'- dimethylphenyl)-1-methyl-propyl]-amine which hydrochloride thereof from alcohol melts at 227-228 C., and which fl-hydroxy-ethane-sulfonate thereof melts at 190- 192" C.;

(g) Ethylamine: N-ethyl-3-(4'-tert.butyl-3' hydroxy- 2,6'-dimethylphenyl)1-methyl-propylamine which melts at l10-1l1 Cl and which hydrochloride thereof from alcohol/ether melts at 184-185 C:

In a similar manner there is obtained by reaction of 4-(4-tert.butyl-2,6-dimethylphenyl)-butane-2-one (produced from 4-tert.butyl-2,6-dimethylbenzyl-chloride and acetoacetic ester) with:

(h) 3,3-diphenylpropylamine: 3 (4' tert.butyl-2',6'- dimethylphenyD-l-methyl N (3',3 diphenylpropyl)- propylamine which hydrochloride thereof from acetone/ petroleum ether melts at 184186 C.; l

(i) 1 methyl 3,3 -diphenylpropylamine: .3 (4'-tert. butyl-2,6'-dimethylphenyl) 1 methyl N (1'-methyl- 3',3'-diphenylpropyl)-propylamine, the hydrochloride of the race-mate mixture melts at 97-103 C.

Example 17 Example 18 From 12.5 g. of 3-(4-tert.buty1-3'-hydroxy-2',6' dimethylphenyl)-1-methylpropylamine (produced from (4'-tert.butyl-3-hydroxy 2 ,6' dimethylphenyl)-butane- 2-one'by reaction with ammonia with subsequent hydrogenation) and- 6.6 g. cinnamic aldehyde, the corresponding Schiff base is produced, which isthen hydrogenized with 2 g. platinum oxide in 500 ml. methanol under normal pressure and at room temperature. After filtration and concentration of the hydrogenated solution, the residue is dissolved in 400 ml. petroleum ether and is reacted with the corresponding amount of alcoholic methyl-sulfonic acid solution. The precipitate "is recrystallized from alcoholic petroleum ether, yielding 14 g. '3-(4-tert.butyl-3' hydroxy 2',6' dimethylphenyD-l- 'methyl-N-(3'-phenylpropyl) propylamine-hydrochloride melting at 194-195 C.

In an analogous manner there is produced by reaction of 3-(3',5-di-tert.butyl-4-hydroxypheny1) propylamine (produced 'by reaction of 3,S-di-tert.butyl-4-hydroxy- 'propylamine, the hydrochloride of which melts at 168- (c) Cinnamaldehyde: N-(3'-phenyl-propyl)-3-(3",5"-

'di-tert.butyl-4"-hydroxy-phenyl)-propylamine, B.P. 186- 190 C./ 0.2 mm. Hg, the hydrochloride melting at 138- 140 C."

(d) B enzaldehyde: N -benzyl-3 3 ,5'-di-tert.butyl-4'- 'hydroxyphenyl)-propylamine, the hydrochloride of which melts at l94196 C.; i

(e) Benzylmethylketone: N (1 methyl 2' phenylethyl) 3 (3",5" di-tert.butyl 4" hydroxyphenyl)- propylamine, the hydrochloride of which melts at 161- Example 19 28 g. N-acetyl-4-tert.-amyl-3-hydroxy-2,6-dimethylphenethylarnine are reacted with LiAlH. in tetrahydrofuran and Worked up as in Example 9. The raw base is converted into its hydrochloride, which, after recrystallization from alcohol-ether, melts at 242-24490.

The required starting material is produced by reacting 2,4-dimethylphenol with trimethyl-ethylene to produce 2-tert.amyl-4,6-dimethyl-phenol which is then chloromethylated, reacted with. NaCN, hydrogenated, and

'acetylated with acetic anhydride; a

, Example 20 A g By analogy to Example 19, 29 g. N-acetyl-3 hydroxy 2,6-dimethyl-4- (3 -methylpentyl-3' -phenethylamine with LiAlH are converted into N-ethyl-3-hydroxy-2,6-

dimethyl-4- 3 '-methylpentyl-3 -phenethylamine, produc- ,ing 21 g. of the hydrochloride which after recrystallization from methanol/ether melts at 263-265 C. with decomposition. v e V 1 As in Example 19, the starting material can be obtained from 2,4-dimetl1ylphenol and 3-methyl-pentene-(2). 1.

-' Example 21 I g The Schiff base which is produced from 5 g. 3-hydroxy- 2,6-dimethyl-4-(3'-rnethylpentyl-3)- phenethylamine and '5 g. 4,4-diphenyl-butane-Z-one is hydrogenated with l g. -Pt0 under normal'pressure' and at room temperature; After the catalyst is filtered olf and the methanol distilled off, the residue is treated with ether andHCl to convert it into the hydrochloride which after recrystallization from methanol-ether yields 5.5 g. of 3-hydroXy-2,6-dimethyl 4 (3-methylpentyl-3) N (1-methy1-3',3"-di.- phenylpropyl)-phenethylamine-hydrochloride which melts at 250-252 C. p

' Example 22 3.5 g. 4-tert.butyl-phenethylamine (J. Org. Chem.,

23, p. 1979 (19 58)), 4.5 g. 30% formaldehyde solution and 5 g. formic acid are heated onja steamgbath about 10 minutes. The reaction mixture is poured upon 5 10% NaOH solution. The base is taken up in e'ther and. the aqueous solution shaken out once more with et ea, After drying and concentrating the ether solution; the raw j base is converted into the hydrochloride in the usual rnanner, producing 3 g. of 4'-tert.butylN,N-dimethyl phenethylamine-hydrochloride which melts at 227-229.? .C. I A

mixture is then boiled 4 hours under reflux, the surplus of LiAlH decomposed with aqueous tetrahydrofuran, and the reaction mixture poured on ice and dilute hydrochloric acid. The solution is reacted with 10 g. tartaric acid, and into it is then stirred a large excess of ice cold concentrated NaOH solution. After extraction with ether and preparation in the usual manner, the raw base is obtained and is distilled in vacuum. The fraction which passes over between 205 and 210 C./ 0.05 mm. Hg is converted into the hydrochloride with ether and HCl. The yield is g. N-ethyl-N-[3-(4'-tert.butyl-2',6'-dimethylphenyl)-1- methyl propyl]-N-(1-methyl-3,3-diphenylpropyl)-aminehydrochloride which is obtained in amorphous form by precipitation from ethyl/ acetate/ petroleum ether, and melts with rapid decomposition at 100-102 C.

Example 25 9.2 g. 3-(4-tert.butyl-3'-hydroxy-2,6-dimethylpheny1)- 1 methyl-N-(1-methyl-3,3-diphenylpropyl)-propylamine (racemate I) are first acetylated with acetic anhydride, and then reduced with LiA1H as in Example 24. The raw base is dissolved in petroleum ether, is acidified with HCl in ether, and the solvent then completely distilled off. The hydrochloride is recrystallized from ethyl acetate and 50% ethanol. The yield is 5.5 g. N-ethyl-N-[3-(4-tert.butyl-3'-hydroxy-2',6'-dimethylphenyl)-1-methyl propyl] N (1 methyl-3,3-diphenylpropyl)-amine-hydrochloride, M.P. 202204 C.

The racemate II of this end product is obtained from the racemate II of the starting material in a similar manner. After recrystallization from 50% ethanol, it melts at 204-206 C. Mixture melting point with racemate I: 183-188 C.

Example 26 5.5 g. (2-(4-tert.butyl3'-hydroxy-2',6'dimethylphenyl) l-methyl-N-3,3-diphenylpropyl)-ethylamine, 2.5 g. ethylene oxide, 0.5 ml. water and 50 ml. benzene are heated 20 hours to 200 C. in a bomb tube. After cooling, the solvent is drawn oil under reduced pressure to dryness. The yield is 5 g. N-[2-(4'tert.butyl-3'-hydroxy2,6'-dimethylphenyl) 1 methylethyH-N-(fl-hydroxyethyD-N- (3,3-dipheny1propyl)-amine, which after recrystallization from cyclohexane-petroleum-ether melts at 125126 C.

Example 27 N-( l-methyl-3,3-diphenylproyl)-amine] which is then recrystallized from ethyl acetate and 50% ethanol. The

yield was 7 g.; M.P. 194-1 95 C.

Example 28 15 g. N-propyl-3-(3',5-di-tert.butyl-4'-hydroxyphenyl)- propylamine are hydrogenated with 5 g. 35% formaldehyde in 200 ml. methanol in the presence of 10 g. 5% palladium charcoal at room temperature and under normal pressure. The solution after being freed from catalyst is evaporated down under reduced pressure and the raw base (14.9 g.) is then distilled under a high vacuum. The yield is 10.1 g. of (66% theoretical) N-methyl-N- propyl 3 (3',5 di-tert.butyl-4hydroxyphenyl)-propyl amine, B.P. 134137 C;/0.01 mmpHg.

Example 29 11 g. 4 tert.butyl-N,2,6-trimethyl-phenethylamine are boiled 55 hours under reflux with 8 g. Raney nickel. and

ml. absolute alcohol. After" cooling the icatalyst is Example 30 22.9 g. 3 (4-tert.butyl-3'-hydroxy 2',6'-dimethylphenyl)"- 1 methyl-N-(1-methyl-3,3-diphenylpropy1)-propylamine (racemate I), 8.7 g. 35% formaldehyde solution and 14 g. formic acid are reacted in a manner analogous to Example 22. The residue is treated with HCl in petroleurn ether/ ethyl ether, the solvent distilled off, and the amorphous hydrochloride dissolved in 400 ml. benzene. After 15 to 20 minutes of boiling over a steam bath, the crystalline hydrochloride separates out, and after recrystallization, from ethyl acetate, it melts at 205-206" C. The yield is 20 g. N-[3-(4'-tert.butyl-3'-hydroxy-2,6'-di methylphenyl) l-methylpropyl]-N-methyl-N-(l-methyl- 3,3 diphenylpropyl)-amine-hydrochloride (racemate I). The analogous racemate II which is obtained in a. similar manner can be recrystallized as the hydrochloride from benzene and petroleum ether, and melts with decomposition at 132-135 C. I

Example 31 29.1 g. N,N diethyl-ot-(4-tert.butyl-3-hydroxy-2,6-di- .methylphenyl)-acetamide, (produced by saponifying 4- tert.butyl-3-hydroxy-2,6-dimethyl-benzylcyanide to 4-tert. butyl 3 -'hydroxy-2,6-dirnethyl-phenyl-acetic acid, M.P. 168-169" C., which is treated with thionyl chloride and the acid chloride, and then reacted with diethylamine) are dissolved in m1. absolute tetrahydrofuran and during cooling with ice are added dropwise to a suspension of 12 g. LiAlH in 300 ml. absolute tetrahydrofuran. The reaction mixture is then boiled 7 hours under reflux. After decomposition of the excess LiAlH with watercontainingtetrahydrofuran, the mixture is poured upon 2.5 liters of ice water, is acidified with an excess of 25% hydrochloric acid, and is extracted with ether. The aqueous acid solution is reacted with 50 g. tartaric acid, is stirred into a large excess of ice cold concentrated NaOH solution, and the alkaline solution is extracted with ether. The basic compounds thus obtained are recrystallized from petroleum/ ether. The yield is 8 g. N,N-diethyl-4- tert.butyl 3-hydroxy-2,G-dimethyl-phenethylamine, M.P. 100.102 C. 1

- Example 32 By analogy to Example 24, from 3-(4'-tert.butyl-3'- hydroxy 2,6' dimethylphenyl) 1 methyl 4 N (1 methyl-3,3-diphenylpropyl)-propylamine (racemate I) by reaction with propionic anhydride and subsequent reduction with LiAlH there is obtained N-[34'-tert.butyl-3- hydroxy 2',6' dimethylphenyl) 1 methyl-propyl] N (1 methyl 3,3 diphenyl propyl) N -(n -'propyl) amine, which after conversion into the hydrochloride is recrystallized from benzene and petroleum ether or acetone. The salt melts at 166 C. After solidification it melts the second time at 221-223 C. with decomposition.

From the same starting materials, but by reaction with butyric anhydride and subsequent reduction with LiAlH there' is obtained N-[3-(4-tert.butyl-3'-hydroxy-2',6-dimethylphenyl) 1 methyl propyl] N (l methyl 3,3-diphenyl-propyl) -N-(n-butyl) amine.

a I Example 33 7 is refluxed for 3'hours. is separated.

residue is. dissolved in ethyl acetate.

22.5 g. of 4-tert.butyl-3-hydroxy-N,N,2,6-tetramethylphenethylamine-hydrochloride, which after recrystallization -froin alcohol-ether melts at 250-252? C.

By an analogous reaction, from 20.5 g. 4-tert.butyl-2,6-

I dimethyl-phenethylamine, there are' obtained '21 g. of 4- tert.butyl N,N,2;6-tetramethylphenethylamine hydrochloride, whichmelts at 275-278 C. with'decornposition. V it )7 y V a 451g. or 3 4"- tertbutyl 3' hydroxy-"2'6' didiphenylpropyl) -.p'ropylamirie (racemate I) are dissolved separator. 15.5 g'.-of diethyl sulfate and 10.1 g. of diisopropylamine are addedto the boiling solution which is refluxed for 2'hours. Subsequently, 7.8 'g. of diethyl sulfate and 5.0 g. .di-isopropylamine are added; after' refluxing for another 2 hours, 7.8 g. of diethyl sulfate and f=5.0 f g. of di isopropyl amine are added and the solution 7 Upon every addition, some water After being cooled, the xylene solutionfis' separated from the insoluble material. The xylene is evaporatedunder reduced pressure .and the residue is taken up with ether. The ethereal solution is washed with dilute sodium hydroxide and water and is dried and concentrated. The t h v t The solution is acidified with ethereal hydrogenchloride and is refluxed ,methylphenyl) 1 7 methyl N (1 methyl 3,3

V jin'300 ml. xylene and refluxed in a vessel with Water for some minutes. TheN;ethyl-N-[3-(4-tert.butyl-3' hydroxy 2',6 dimethylphenyl) 1; methyl propyl] 'N L (1 methyl 3,3 diphenylpropyl) amine-hydrochloride'crystallizes 'andis recrystallized from alcohol/ ethyl acetate; 204;206 c. 7 xam le 35 .5 g.of'VN,O-di acetyl-Nrethyl 4ftert.butyl-3-hydroXy-2 .d-dimethylphenethylamine are refluxed for 5 hours with "100 ml. of 16% aqueoussodium hydroxide. 'The reac- 7 tion mixture is diluted with twice the quantity of water and -extracted with etherf. The residue from the ethereal solution is worked'up in the usual way and converted into the. hydrochloride whereby 3.5 g..of N,N-diethyl- 4- tert.buty l 3 hydroxy 2 ,6 dimethylphenethylarninehydrochloride are obtained which are recrystallized from alcohol/ether, '263 C.,(decomposition).

V I :5 g. of 3 acetoxy-Nthylr4-tert.butyl N,2,6-trimethyl j phenethylamine-hydrochloride arejrefluxed for 5 hours in 150 ml. ofmethanolici'KOH (10%); The reaction mixture is diluted 7 With icewater. The base. is isolated ethanol. MP. 205 208? c.

Example 38 Y V 52.6 g. of y-(3,5-di-tert.butyl-4-hydroxy-phenyl)-pro- :pylarnine are dissolved in 500 ml. of ethanol and hydro: genated under about 3 atm. at 60C. in the presence of V '100 g. of formaldehyde and 5 g. of PtO The catalyst is filter-ed off and the solution is evaporated. The

'crude base (53 g.) is taken. up with ether and converted into the hydrochloride by addition of ethereal hydrogen chloride. Upon recrystallization from alcohol, the N,N

propyl]amine-hydrochloride melts at 178-481 C. 1 ,The base obtained from the way melts at 3 1-33 C.

The starting material is obtained from 2 6 -di-tert.butyl- V phenol as indicated in Example 37;

Example 39 yl-ketone are'dissolved. in 200 ml. of'ethanol and'hydro gen-ated under 115 atm. and at l30 C. in the presenceof V I 10 got ethyl amine and.5 g. of Raney Ni. 'T he catalyst is filtered oil and the solution is evaporated Tawny; residue is treated with 50 ml.of dilute'hydrochloric acid and extracted with ether.

alkaline and extracted with ether. The combined ether 7, extracts are dried with sodium sulfate and evaporated; 6. 8 g. of oily 2-ethylamino-1-(3i-tert.butyl-4f-hydroxy5 5 -methylphenyl.)-propane are obtained which are con- The aqueous layer, is made Verted .into the hydrogen-fumarate by addition of the calculated amount of fumaric "acidinBO ml. of absolute The base maybe obtained manner. It is recrystallized from cyclohexane/petroleum' ether. M.P.100-102C. a

terLbutyl-phenol is reacted with propionyl chloride. .The .phenol ester thus obtained is saponified to form 3-tert. bu .tyl-A-hydroxy-5*methyl-pr0piophen0ne, M.'P. 130-132? C.' Reaction with'bromine results in' the formation of oc-i 4O bromo-3-tert.butyl-4-hydroxy ,5 methyl propiophenone Preparation "of the startihg matrial.'2-methyl-6 which yields in a known manner the correspondingly sub stituted' a-amino ketone; Thls one ishydrogenated to in the usual wayby extraction with ether" and converted V 7 into the hydrochloride.- 4.0 g. 0f'N-ethyl-4-te1tbutyl-3- hydroxy N,2,6 1 trimethylphenethylamine hydrochloride are obtained melting at225+227 C. upon recrystallization from alcohol/ether. r i

(3'. tertl butyl 4" 'hydroxy Preparation of the starting form the corresponding amino ethanol which is reacted. with phosphorous oxychloride whereby the (3-'tert.butyl-4 hydroxy 5 methylbenzyll: methyl ketone is obtained. 7 i i I t 7 Example 5. V 11.2 of 4 tert.butyl-3-hydroxy-2,6dimethylbenzyl cyanide in-4Q.ml. of methanol are hydrogenated in the presence of 10 g. of 1 0% Pd-coal and 15 g.'of ethyl amine under about 6 atrn.jat C.. The catalyst is filtered oh. 7

The solution is evaporated under reduced pressure. The

residue isdissolved in 60- ml. of ether; ml. of 10% hydrochloric acid are added whereby the N-ethyl-4-tert;-

ibutyl-3-hydroxy-2,6-dimethylphenethylamine hydrochloride is precipitated. Upon recrystallization from methtertbuty-l-plienoliis reacted in the usual way.withN ni-ethyl .for'man'ilide to form 3-tert.butyl 41hydroxy-5 rmethyl ben'zaldehyde which upon reaction with cyanace'ticacid 'yields': theconrespondingly substituted 'cinnamic acidnh 5 trile; Reduction with Raney Ni results. in the formation 7 Q-According tothe-method described in 4Htert.butyl 3-hydroxy-2,6-dimethylphenethylamineiis re? i acted with '4,4-bis7(para-tert.butyl-phenyl).-butane 2rone to for-rd 4 '-tert.butyl-3-hydroxy-2,6dimethyl-N-[3,3-bisano1/e-ther,.10 g. of this product having a'M.P. of-266f 268 C. (decorhp) are obtained. 7

V 7 Example 41 ara terhbutyI-PhenyI) l-methylpropyl]-phenethylainine:

The butanone used ass'tartingmateriaI isobtained by reaction of para-tert;butyl-benzaldehyde with acetone and subsequent addition oi .tertbutylbenzeneto the substituted 1 Exizhtple 42 V According to the methoddesciihedin Example 22,.the1 N- 4-ter-t.butyl"-3 liyd roxy-2,' 6-dimcthylphene'thyl )'-N- [3 3 bis.-(para-tertbutyl-phenyl)}1 methylpr0pyl]g Ngmethyli j hydrochloride inthe usual from the salt in the usual Example 4(a), I. V

R1 R4 Re and the acid addition salts thereof, wherein R is selected from the group consisting of hydrogen,

methyl and ethyl;

R is selected from the group consisting of hydrogen,

phenyl and X;

R is selected from the group consisting of phenoxy,

hydrogen, phenyl, and X;

R; is selected from the group-consisting of hydrogen, alkyl of 1-4 carbon atoms and hydroxyalkyl of l-4 carbon atoms;

X is a substituted phenyl radical of the formula:

R is a tertiary alkyl group vor 4-6 carbon atoms;

R is selected from the group consisting of hydrogen and a tertiary alkyl group of 4-6 carbon atoms;

R and R are each selected from the group consisting of hydrogen and a primary alkyl of 1-4 carbon atoms;

R is selected from the group consisting of hydrogen and hydroxy, with the provision that when R is hydroxy it is in other than the 2- or fi-position, and at least one of R R and R is other than hydrogen;

Y is an alkylene group of l-3 carbon atoms;

m is an integer from 0 to 1 inclusive; .and

n is an integer from 1 to 3 inclusive, with the provision that the group (CH CHR contains less than 5 carbon atoms in total.

2. N propyl 3 (3',5' di tertbutyl 4' hydroxyphenyl -propylamine.

3. N (3' phenylpropyl 3 (3",5" di terhbutyl- 4"-hydroxyphenyl) -propy1 amine.

4. 4 terLbutyl 3 hydroxy N,N,2,6 tetramethylphenethylamine.

5. N ethyl 4 tert.butyl 3 hydroxy N,2,6 trimethyl-phenethylamine.

6. 2 (4 tert.'butyl 3' hydroxy 2',6 dimethylphenyl)-N,N,l-trimethyl-ethylamine.

7. 3 (4' tertbutyl 3' hydroxy 2,6 dimethylphenyl)-N,N,1-trimethyl propylamine.

8. N [3 (4' tert.butyl 2',6' dimethylphenyl) 1- rnethyl propyl] N methyl N (1 methyl 3,3 dipheny-lpropyl) -amine.

9. 4 tertamyl 3 hydroxy N,N,2,6 tetramethylphenethylamine.

10. N ethyl 4 tertamyl 3 hydroxy N,2,6 trimethyl-phenethylamine.

11. -N ethyl 2 (4' tertbutyl 3' hy-droxy 2',6- dimethylphenyl) -N, l-di-methyl-ethyl amine.

12. N ethyl N [3 (4' tert.butyl 3' hydroxy- 2, 6' dimethylphenyl) 1 methyl propyl] N (lmethyl-3,3-diphenylpropyl)amine-hydrochloride.

13. N methyl N propyl 3 (3',5' di tert.butyl- 4'-hydroxyphenyl) -propylamine.

14. N [3 (4' tertbutyl 3' hydroxy 2', 6' dimet-hylphenyl) 1 methyl propyl] N methyl N- 1-methyl-3,3-diphenylpropyl) -.amine-hydrochloride.

References Cited by the Examiner UNITED STATES PATENTS 2,48 0,754 8/49 McCarthy.

2,879,294 3 5 9 Campbell 260-570 2,892,75 3 6/ 59 Schmidt et a1. 167-65 2,971,887 2/ 61 Johnson 167-65 3,116,330 12/63 Krohs et a1. 260570 CHARLES B. PARKER, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3, 202 711 August 24 1965 Wolfgang Fruhstorfer et a1.

corrected below.

Column 7, line 8, for "zine" read zinc column 9, line 26, for "start-" read starting line 28, for "Shiff's" read Schiff's line 67, for "opticially" read optically column 19, line 2, for "N,N,2,6tetramethyl phenethyl read 2,6-dimethyl-phenethylline 13, for "hydroxy," read hydroxylines 35 and 46, for "-diphenylpropyl-", each occurrence, read -diphenylpropyl)- same column 19, lines 40, 61 and 63, for "tert,", each occurrence, read tert. line 58, for "-dimethylphenyl-" read dime'thylphen'yl) column 21, line 47, for "yll-methyl" read yl)-l-methyl column 22, line 54, for "N- [S-4 read N- [3- (4- Signed and sealed this 26th day of April 1966.

(SEAL) Attest:

ERNEST W. SWIDER Attesting Officer EDWARD J. BRENNER Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF AN AMINE OF THE FORMULA 